More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.

Huntington’s disease community will 'get there' in search for therapies, CHDI chief scientist declares after ‘terrific’ conference

 

After presiding over a “terrific” research conference, CHDI Foundation Chief Scientific Officer Robert Pacifici, Ph.D., declared that the Huntington’s disease community will “get there” in the search for long-awaited therapies.

 

Dr. Pacifici commented in an interview with me on March 1, after the CHDI-sponsored 19th Annual HD Therapeutics Conference, held in Palm Springs, CA, from February 26-29.

 

The CHDI chief scientific officer (CSO) provided his optimistic assessment in referencing the featured presentation by David Altshuler, M.D., Ph.D., CSO of the Boston-based Vertex Pharmaceuticals.

 

“They’ve solved some unbelievably difficult problems,” Dr. Pacifici said of Vertex, noting that it found a cure for hepatitis C.

 

Vertex has also developed therapies for three tough diseases that, like HD, are genetic: cystic fibrosis, sickle cell disease, and transfusion-dependent beta thalassemia.

 

At future therapeutics conferences, “we would love for the last talk” to focus on a new drug that is “now going to be approved,’” Dr. Pacifici told me.

 

“We’re going to get there,” he continued. Dr. Altshuler, who Dr. Pacifici said carefully calibrates his optimism, “was very complimentary and very confident that if we stay on this path, we’ll actually achieve that. He felt that the collective efforts that CHDI is trying to catalyze throughout the community are going to be successful.”

 

Dr. Pacifici pointed out how CHDI has adhered to another key principle of drug discovery emphasized by Dr. Althsuler: studying HD in human cells, tissues, and postmortem samples.

 

Dr. Pacifici said he expects the HD field will hear more from Dr. Altshuler and welcomed Vertex’s possible revived involvement.

 

In 2010 I spoke on my family’s fight against HD at the Vertex labs in San Diego and chronicled its search at the time for an HD therapy, though so far without results reported by that lab.

 

Dr. David Altshuler presenting a timeline of Huntington's disease scientific landmarks at the 19th Annual Therapeutics Conference, February 28, 2024. Pictured in the slide is James Gusella, Ph.D., whose lab discovered the huntingtin genetic marker in 1983 and the gene in 1993 (photo by Gene Veritas, aka Kenneth P. Serbin, and posted with permission of CHDI Foundation). (Click on the image to make it larger.)

 

The need to celebrate milestones

 

“But I think what you will see is incremental successes,” Dr. Pacifici continued. “We’re going to have these new findings, these critical milestones and stepping stones along the way that we should embrace and celebrate and use those as a source of hope that, even though it never moves as fast as we would like, we’re making very real, tangible progress”

 

Dr. Pacifici described the 19th conference as “terrific,” noting that more than 450 people – a record – 50 companies, and 70 academic institutions took part. He recalled how no biopharma firms attended the first few conferences. Now such companies “come to a conference because they think an area is ripe for discovery,” he observed.

 

“Everybody commented on how quickly the conference went this year,” Dr. Pacifici said. “There was just so much information and so much happening and actually people were sad when it was over.”

 

I found this, my twelfth CHDI conference, particularly exhilarating because of the amount of new data and the high quality of the presentations.

 

A virtual nonprofit biotech, CHDI is the largest private funder of HD research. As in our interviews at past therapeutics conferences, Dr. Pacifici summarized the key findings of the scientists’ presentations. Watch our 39-minute interview in the video below.

 

 

Key developments

 

Dr. Pacifici explained several key developments.

 

The session on new data and insights into the basic biology of HD included presentations that help “to understand exactly how we can custom craft the profile of candidate drugs to make sure that they hit the right things and are as safe as possible,” Dr. Pacifici said. Such crafting would mean that drugs could effectively address the numerous specific problems in HD, he added.

 

Another session “shined a bright light” on DNA repair, modifier genes, and somatic instability, the tendency of the deleterious expansion of the DNA to worsen with age and therefore trigger disease onset, Dr. Pacifici said. The new findings can contribute to the ongoing effort to “manipulate” these processes to slow or stop instability and therefore prevent the disease, he explained.

 

Including talks detailing HD at the cellular and molecular level, the session titled “It’s a Brain Disease” was “unbelievably informative” about specifying how HD harms the brain, Dr. Pacifici said.

 

Clinical trial news and the importance of participation in research

 

The final session featured clinical trial updates from uniQure, PTC Therapeutics, and Roche. None of these has yet reached Phase 3, the definitive test of a drug.

 

Referring to the 2021 results of Roche’s first attempt at a Phase 3 trial, Dr. Pacifici noted that the firm’s scientists “have really gone to town and reanalyzed the samples, reanalyzed the data in a way that is hopefully going to teach us not only why that particular trial didn’t meet its endpoints” but also “what we can do differently.” Roche’s reassessment of its drug, tominersen, in a Phase 2 trial, GENERATION HD2, is in progress.

 

Ultimately, the field needs a “conveyor belt” of new drug possibilities to develop the multiple kinds of drugs necessary for treating different aspects of HD, Dr. Pacifici concluded. Not all those new drugs will be successful, he said, but the more produced, the greater likelihood for successful therapies.

 

Dr. Pacifici pointed out that many of the discoveries discussed at the meeting resulted from the human data collected from tens of thousands of research volunteers.

 

Future projects and breakthroughs will continue to rely on large numbers of participants, he said. Some individuals may carry unique genetic characteristics revealing new kinds of therapies.

 

“Hang in there,” Dr. Pacifici said in his closing comment for the HD community. “I hope that next year at the 20th [conference] we’ll have some more good news to communicate.”

 

Stay tuned for further news from the conference!